Recent research suggests a role for the hypothalamic-pituitary-adrenal (HPA) axis in the behavioral effects of cocaine. Cocaine induces glucocorticoid release (e.g., corticosterone, ACTH) probably due to corticotropin releasing factor (CRF). In general, treatments that increase levels of these hormones enhance some behavioral effects of cocaine, whereas treatments that decrease levels of these hormones attenuate some of these effects. This includes stressor exposure that activates the HPA axis and amplifies the behavioral effects of cocaine. And, greater behavioral responsivity to cocaine has been related to inherently high HPA axis hormone levels. Inherent differences in HPA axis function exist between two inbred strains, lewis and Fischer 344 (F344) rats, which also differ in their behavioral and biochemical responses to psychoactive drugs. Lewis rats, compared to F344 rats, exhibit enhanced sensitivity to and preference for cocaine. These strains also differ in several biochemical characteristics of the mesolimbic dopamine system, a neural area associated with drug responses. Paradoxically, Lewis rats have blunted HPA hormonal activity and impaired autoimmune responses. That HPA axis hormones interact with the immune system (e.g., ACTH induces release of some cytokines) may have important implications for the relationship of immunological diseases, such as HIV infection, and cocaine abuse. This grant will compare how various manipulations of the HPA axis (e.g., glucocorticoid administration adrenalectomy, CRF antiserum and antagonist administration, stress exposures) affect the neurobehavioral responses to cocaine in Lewis and F344 rats; these strains provide models both to study interactions of the neuroendocrine and immune systems and to study vulnerability to drug abuse. Behavioral measures will include locomotor activity, place conditioning, drug discrimination, and self-administration. Biochemical measures will include many signal transduction proteins (e.g, tyrosine hydroxylase, protein kinase A) regulated specifically in VTA/NAcc by chronic drug or stress exposure. In addition, levels of ACTH-related cytokines will be assessed. These studies may provide insight into possible differing etiologies and treatment approaches for cocaine abuse.